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Molecular Microbiology Jun 2024Bacterial chromosomes are large molecules that need to be highly compacted to fit inside the cells. Chromosome compaction must facilitate and maintain key biological... (Review)
Review
Bacterial chromosomes are large molecules that need to be highly compacted to fit inside the cells. Chromosome compaction must facilitate and maintain key biological processes such as gene expression and DNA transactions (replication, recombination, repair, and segregation). Chromosome and chromatin 3D-organization in bacteria has been a puzzle for decades. Chromosome conformation capture coupled to deep sequencing (Hi-C) in combination with other "omics" approaches has allowed dissection of the structural layers that shape bacterial chromosome organization, from DNA topology to global chromosome architecture. Here we review the latest findings using Hi-C and discuss the main features of bacterial genome folding.
PubMed: 38922728
DOI: 10.1111/mmi.15290 -
Gastric Cancer : Official Journal of... Jun 2024Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair... (Review)
Review
Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.
PubMed: 38922524
DOI: 10.1007/s10120-024-01523-4 -
Journal of Fungi (Basel, Switzerland) Jun 2024In budding yeast, Rad5 and Rad7-Rad16 play respective roles in the error-free post-replication repair and nucleotide excision repair of ultraviolet-induced DNA damage;...
In budding yeast, Rad5 and Rad7-Rad16 play respective roles in the error-free post-replication repair and nucleotide excision repair of ultraviolet-induced DNA damage; however, their homologs have not yet been studied in non-yeast fungi. In the fungus , a deficiency in the Rad7 homolog, Rad5 ortholog and two Rad16 paralogs (Rad16A/B) instituted an ability to help the insect-pathogenic fungus to recover from solar UVB damage through photoreactivation. The fungal lifecycle-related phenotypes were not altered in the absence of , or while severe defects in growth and conidiation were caused by the double deletion of and . Compared with the wild-type and complemented strains, the mutants showed differentially reduced activities regarding the resilience of UVB-impaired conidia at 25 °C through a 12-h incubation in a regime of visible light plus dark (L/D 3:9 h or 5:7 h for photoreactivation) or of full darkness (dark reactivation) mimicking a natural nighttime. The estimates of the median lethal UVB dose LD from the dark and L/D treatments revealed greater activities of Rad5 and Rad16B than of Rad16A and additive activities of Rad16A and Rad16B in either NER-dependent dark reactivation or photorepair-dependent photoreactivation. However, their dark reactivation activities were limited to recovering low UVB dose-impaired conidia but were unable to recover conidia impaired by sublethal and lethal UVB doses as did their photoreactivation activities at L/D 3:9 or 5:7, unless the night/dark time was doubled or further prolonged. Therefore, the anti-UV effects of Rad5, Rad16A and Rad16B in depend primarily on photoreactivation and are mechanistically distinct from those for their yeast homologs.
PubMed: 38921406
DOI: 10.3390/jof10060420 -
Journal of Fungi (Basel, Switzerland) May 2024DNA damage checkpoints are essential for coordinating cell cycle arrest and gene transcription during DNA damage response. Exploring the targets of checkpoint kinases in...
DNA damage checkpoints are essential for coordinating cell cycle arrest and gene transcription during DNA damage response. Exploring the targets of checkpoint kinases in and other fungi has expanded our comprehension of the downstream pathways involved in DNA damage response. While the function of checkpoint kinases, specifically Rad53, is well documented in the fungal pathogen , their targets remain poorly understood. In this study, we explored the impact of deleting on the global transcription profiles and observed alterations in genes associated with ribosome biogenesis, DNA replication, and cell cycle. However, the deletion of only affected a limited number of known DNA damage-responsive genes, including and . Unlike , the downregulation of transcription in under the influence of Methyl Methanesulfonate (MMS) did not depend on Dun1 but still relied on Rad53 and Rad9. In addition, the transcription factor Mcm1 was identified as a regulator of transcription, with evidence of dynamic binding to its promoter region; however, this dynamic binding was interrupted following the deletion of . Furthermore, Rad53 was observed to directly interact with the promoter region of , thus suggesting a potential role in governing its transcription. Overall, checkpoints regulate global gene transcription in and show species-specific regulation on ; these discoveries improve our understanding of the signaling pathway related to checkpoints in this pathogen.
PubMed: 38921373
DOI: 10.3390/jof10060387 -
Molecular Cancer Therapeutics Jun 2024Poly (ADP-ribose) polymerases 1 (PARP1) is a critical enzyme involved in DNA damage repair. It belongs to a super family of proteins and catalyzes poly...
Poly (ADP-ribose) polymerases 1 (PARP1) is a critical enzyme involved in DNA damage repair. It belongs to a super family of proteins and catalyzes poly (ADP-ribosyl)ation (PARylation). PARP1 inhibitors are effective to treat tumors that have homologous recombination deficiency (HRD) such as the ones with BRCA1/2 mutations. The PARP1 inhibitors that have been approved by FDA inhibit both PARP1 and PARP2. PARP2 has also been suggested to have similar function in DNA repair as PARP1. In addition to inhibiting PARP1 enzymatic activities, PARP1 inhibitors also cause PARP1 enzyme to be "trapped" on DNA which leads to DNA replication fork to stall and eventually double-strand DNA breaks and cell death. Here, we report a PARP1 inhibitor, Senaparib, which has a novel chemical structure and high potency inhibiting PARP1/2 enzymes. Senaparib was highly potent in cell viability tests against tumor cells with BRCA1/2 mutations. It was efficacious in CDX and PDX xenograft models in tumor harboring BRCA1/2 mutations. In combination studies, Senaparib used with temozolomide (TMZ) had shown strong synergistic cytotoxicity in both in vitro and in vivo experiments. Senaparib represents a novel class of PARP1 inhibitors that can be used for the treatment of cancer. A phase III clinical study of Senaparib for maintenance treatment following first-line chemotherapy in patients with advanced ovarian cancer has met its primary endpoint, and a new drug application of Senaparib has been accepted by National Medical Products Administration (NMPA) of China for review.
PubMed: 38920409
DOI: 10.1158/1535-7163.MCT-23-0625 -
Frontiers in Genetics 2024Fracture healing is a complex process that involves multiple molecular events, and the regulation mechanism is not fully understood. We acquired miRNA and mRNA...
Fracture healing is a complex process that involves multiple molecular events, and the regulation mechanism is not fully understood. We acquired miRNA and mRNA transcriptomes of mouse fractures from the Gene Expression Omnibus database (GSE76197 and GSE192542) and integrated the miRNAs and genes that were differentially expressed in the control and fracture groups to construct regulatory networks. There were 130 differentially expressed miRNAs and 4,819 differentially expressed genes, including 72 upregulated and 58 downregulated miRNAs, along with 2,855 upregulated and 1964 downregulated genes during early fracture healing. Gene ontology analysis revealed that most of the differentially expressed genes were enriched in the extracellular matrix (ECM) structure and the ECM organization. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment suggested cell cycle, DNA replication, and mismatch repair were involved in the progression of fracture healing. Furthermore, we constructed a molecular network of miRNAs and mRNAs with inverse expression patterns to elucidate the molecular basis of miRNA-mRNA regulation in fractures. The regulatory network highlighted the potential targets, which may help to provide a mechanistic basis for therapies to improve fracture patient outcomes.
PubMed: 38919952
DOI: 10.3389/fgene.2024.1408404 -
Frontiers in Immunology 2024The global impact of the SARS-CoV-2 pandemic has been unprecedented, posing a significant public health challenge. Chronological age has been identified as a key... (Review)
Review
The global impact of the SARS-CoV-2 pandemic has been unprecedented, posing a significant public health challenge. Chronological age has been identified as a key determinant for severe outcomes associated with SARS-CoV-2 infection. Epigenetic age acceleration has previously been observed in various diseases including human immunodeficiency virus (HIV), Cytomegalovirus (CMV), cardiovascular diseases, and cancer. However, a comprehensive review of this topic is still missing in the field. In this review, we explore and summarize the research work focusing on biological aging markers, i.e., epigenetic age and telomere attrition in COVID-19 patients. From the reviewed articles, we identified a consistent pattern of epigenetic age dysregulation and shortened telomere length, revealing the impact of COVID-19 on epigenetic aging and telomere attrition.
Topics: Humans; COVID-19; Aging; SARS-CoV-2; Epigenesis, Genetic; Telomere; Telomere Shortening
PubMed: 38919619
DOI: 10.3389/fimmu.2024.1399676 -
Journal of the American Chemical Society Jun 2024Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of...
Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A-C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus . Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.
PubMed: 38918178
DOI: 10.1021/jacs.4c05399 -
RNA (New York, N.Y.) Jun 2024Telomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while...
Telomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while C-strand replication is accomplished by CST-polymerase α -primase (CST-PP). Replication of both strands is inhibited by formation of G-quadruplex (GQ) structures in the G-rich single-stranded DNA. TMPyP4 and pyridostatin (PDS), which stabilize GQ structures in both DNA and RNA, inhibit telomerase in vitro, and they cause telomere shortening in human cells that has been attributed to telomerase inhibition. Here, we show that TMPyP4 and PDS also inhibit C-strand synthesis by stabilizing DNA secondary structures and thereby preventing CST-PP from binding to telomeric DNA. We also show that these small molecules inhibit CST-PP binding to a DNA sequence containing no consecutive guanine residues, which is unlikely to form GQs. Thus, while these "telomerase inhibitors" indeed inhibit telomerase, they are also robust inhibitors of telomeric C-strand synthesis. Furthermore, given their limited specificity for GQ structures, they may disrupt many other protein-nucleic acid interactions in human cells.
PubMed: 38918043
DOI: 10.1261/rna.080043.124 -
Journal of the American Chemical Society Jun 2024The properties of DNA that make it an effective genetic material also allow it to be ideal for programmed self-assembly. Such DNA-programmed assembly has been utilized...
The properties of DNA that make it an effective genetic material also allow it to be ideal for programmed self-assembly. Such DNA-programmed assembly has been utilized to construct responsive DNA origami and wireframe nanoassemblies, yet replicating these hybrid nanomaterials remains challenging. Here we report a strategy for replicating DNA wireframe nanoassemblies using the isothermal ligase chain reaction lesion-induced DNA amplification (LIDA). We designed a triangle wireframe structure that can be formed in one step by ring-closing of its linear analog. Introducing a small amount of the wireframe triangle to an excess of the linear analog and complementary fragments, one of which contains a destabilizing abasic lesion, leads to rapid, sigmoidal self-replication of the wireframe triangle via cross-catalysis. Using the same cross-catalytic strategy we also demonstrate rapid self-replication of a hybrid wireframe triangle containing synthetic vertices as well as the self-replication of circular DNA. This work reveals the suitability of isothermal ligase chain reactions such as LIDA to self-replicate complex DNA architectures, opening the door to incorporating self-replication, a hallmark of life, into biomimetic DNA nanotechnology.
PubMed: 38917418
DOI: 10.1021/jacs.4c04089